There are 22.5 people in the US who have a fragile X mental retardation (FMR1) gene gray zone expansion or lack AGG interspersions in FMR1. Longer expansions in this gene are associated with intellectual disability, autism, infertility, an neurodegenerative disorder in adults, to include tremor and gait ataxia. Recent studies have shown that older individuals with FMR1 gray zone expansions have a higher risk of parkinsonism and lower cognitive function. However, this association has not been conclusively defined. This project will determine: 1) the association of FMR1 gray zone expansions and the presence of movement disorders and cognitive deficits in a community based sample, 2) the relationship of loss of normal AGG interspersions in FMR1 and these neurological phenotypes, and 3) whether neuronal intranuclear inclusions similar to those seen in larger expansion carriers are present in the FMR1 gray zone carriers. To reach these aims, this study will involve analysis of data collected in two large epidemiological cohorts of 2700 subjects total from: the Religious Orders Study (P30AG10161, R01AG15819) and the Memory and Aging Project (R01AG17917). Clinical data related to motor function, movement disorders, and cognitive testing will be analyzed based on the presence or absence of FMR1 gray zone expansion status and the presence or absence of stabilizing AGG interspersions in the FMR1 trinucleotide repeat. In identified FMR1 gray zone carriers, brain sections will be examined for abnormalities typically seen in FMR1 carriers, to include intranuclear inclusions, and compared to age and sex matched controls. If this study does confirm an association between neurological signs, pathological findings, and FMR1 gray zone expansion or loss of FMR1 AGG interspersions, the long term objective is to more concisely define the phenotype genotype relationship and molecular contributors to clinical manifestations, such as secondary gene effects. Results of this study will change the genetic counseling for individuals with FMR1 gray zone expansions. This project addresses the following goals of the 2008 NIH Research Plan on Fragile X Syndrome and Associated Disorders: epidemiology of FMR1 gene variations (FXS), epidemiology in movement disorder populations (FXTAS), and broader implications for other neurodegenerative diseases (FXTAS).